Parkinson's disease is the second most common neurodegenerative disease associated with aging. Mutations in PTEN induced kinase 1 (PINK1) and PARKIN cause autosomal recessive forms and some sporadic cases of Parkinson's disease. PINK1encodes a putative serine/threonine kinase with a mitochondrial targeting sequence, whereas PARKIN encodes a putative E3 ubiquitin ligase. Drosophila melanogaster contains single homologs of pinkl and parkin, and the residues mutated in versions of PINK1 associated with human disease are largely conserved in flies. We have previously shown that loss of pinkl in Drosophila results in male sterility, muscle degeneration and stress sensitivity due to defects in mitochondrial morphology and function. Moreover, pinkl and parkin function in the same genetic pathway, with pinkl positively regulating parkin. In addition, expression of human PINK1 in pinkl mutant flies rescues the pinkl mutant phenotypes, suggesting that human and Drosophila pinkl are functionally conserved. We will study how Pinkl and Parkin interact to regulate mitochondrial function. In addition, we will carry out genetic screens to identify other components of the pinkl/parkin pathway. Many neurodegenerative disorders of aging are associated with mitochondrial dysfunction. The identification of new components in the pinkl/parkin pathway is likely to provide insight in pathogenesis of these diseases, as well as Parkinson's disease, and may identify new diagnostic tools and therapeutic targets. Our long-term goal, which may require collaborations with other labs, is to explore functions of pinkl/parkin pathway components in mammals and to search for potential mutations in these genes in Parkinson's disease patients, and mechanisms by which defects in this pathway can be suppressed. UCLA provides an excellent environment for research on molecular mechanisms of aging- related neurodegenerative diseases. This KO2 award, if funded, will protect the candidate's research time from overextended clinical duties to allow further research development.